Preparation of delta9(11)-anhydro-steroids from 11deta-hydroxy-steroids



United States Patent PREPARATION OF A -ANHYDRO -STEROIDS FROM llfi-HYDROXY-STEROIDS Earl M. Chamh'erlin, Westfield, and John M. Chemerda,

Metuchen, N.J., assi'gnors to Merck & Co., Inc., Rahway, N.J., a corporation of New Jersey No Drawing. Application July 29, 1954 Serial No. 446,664

3 Claims. (Cl. 260-397.45)

This invention relates to the prepar'tion of steroids, and particularly, to the preparation of A -anhydro steroids from 1 lfi-hydroxy-steroids.

It has been suggested to prepare A -anhydrosteroids from llp-hydroxy-steroids by treating with phosphorous oxychloride in pyridine. It has also been suggested to carry out this reaction with a mixture of acetic acid and hydrochloric acid, as well as, with acetic acid alone in the presence of a catalyst, such as, hydrogen bromide. The effectiveness of these various methods depends to a large extent upon the particular 11 fi-hydroxy-steroid employed. In using the phosphorous oxychloride method, an 11 fi-hydroxy-pregnane will be converted to the corresponding A -anhydro-pregnene in relatively good yield, although it usually requires an extended period of time, at room temperature, to complete the reaction. When an 11 B-hydroxy-A pregnene is converted to the corresponding A -anhydro-pregnadiene, the yield, however, is relatively small. A relatively high yield of product may be obtained after extensive reaction time, when the starting material is a compound having keto groups blocked, such as, at the 3 and 20 positions by a ketal formation. An example of this is the conversion of A -pregnene-llp,l7a, 21-triol-3,20-dione-2l-acetate-3,ZO-bis-ethylene ketal to the corresponding A -anhydro-pregnadiene. The use of a mixture of acetic acid and hydrochloric acid results in low yields of A -anhydro-steroid, although the reaction is relatively rapid. Acetic acid with a hydrogen bromide catalyst results in only fair yields and requires an extensive period of reaction time.

It has been suggested to subject llu hydroxy-steroids, after first acylating any 21-hydroxy group, to tosylation to form the corresponding lla-tosylate compound. The latter compound is then reacted with sodium acetate and boiling acetic acid to form the corresponding M -anhydro-steroid. This reaction differs from the reactions mentioned above, in that, it requires two distinct steps to remove the lla-hydroxy group and form a double bond at position 9(11). This method has not been applied to 11 fl-hydroxy-steroids, because when the hydroxy group is in the B configuration it is not subject to acylation, except under such severe conditions as to cause the destruction of the molecule. This is especially the case with a steroid having a l7-position side chain because of the recognized lability of such a side chain, and also with steriods having a double bond at the 4 position which would be expected to undergo reaction.

It is an object of this invention to provide a simplified procedure for converting l1 ,B-hydroxy-steroids to the corresponding A -anhydro-steroid. It is another object to provide such a process whereby the conversion is carried out directly in one step in high yield. It is a further object of the invention to provide such a process, which can be applied to a broad group of steroids, with uniformly good results. Other objects and the advantages of the invention will appear hereinafter.

In accordance with the invention llfl-hydroxy-steroids are converted to the corresponding A -anl1ydro-steroid 'Patented Sept. 15, 1959 by treating with an organic sulfonyl chloride. The or ganic sulfonyl chloride is of the formula RSO Cl, wherein R is an alkyl group preferably having a carbon chain length of from one to eight carbon atoms. This reaction is surprising since the aryl sulfonyl chlorides do not yield the desired product. Typical examples of such compounds which may be mentioned are methanesulfonyl chloride, ethanesulfonyl chloride, propanesulfonyl chloride, butanesulfonyl chloride, heptanesulfonyl chloride, hexanesulfonyl chloride, octanesulfonyl chloride. The lower alkyl (from one to four carbon atom chain) sulfonyl chlorides are distinctly advantageous because the reaction many he carried out at more desirable conditions. The organic sulfonyl chloride is usually used in from one to ten moles per mole of llfl-hydroxy-steroid.

In a preferred embodiment of the invention, the reaction is carried out with the organic sulfonyl chloride in the presence of a tertiary amine type base. Typical examples of classes of such bases are pyridines; N-alkylmorpholines; N-alkyl-piperidines; lutidines; collidines; and trialkylamines. Of particular mention are the more readily available members of these groups, such as pyridine; N-methylmorpholine; N-ethylmorpholine; u,' -h1tidine; collidine; nicotine; trimethylamine; triethylamine; tripropylamine; dimethylaniline; diethylaniline; N-arnylpiperidine; N-butylpiperidine; N-ethylpiperidine; N-methylpiperidine; N-heptylpiperidine; and N-propylpiperidine. The base is preferably present in from one to ten moles for each mole of steroid. The base selected is preferably one that is also a solvent for the llfi-hydroxy-steroid, such as pyridine or lutidine. The ability of any of the bases to act as a solvent for the steroid under the conditions of the reaction may be readily determined by a sim ple solubility test.

The reaction is conveniently carried out in a solvent for the steriod. The solvent, as mentioned above, may also serve as the base. The solvent may also beamixture of a hydrocarbon and a base, such as benzene-pyridine mixture or a mixture of a chlorinated hydrocarbon and a base, such as methylene chloride and pyridine. Other solvents which may be mentioned are dimethylformamide, dimethylacetamide, chloroform, acetone, propylene glycol, methyl ethyl ketone and anhydrous mixtures of these solvents.

The time required for the reaction will depend, in part, upon the particular reactants, solvents, and temperatures. At room temperature of 25 to 30 C., the reaction usually requircs approximately 10 to 18 hours when a lower alkyl sulfonyl chloride is used. At temperatures of from 55 to 60 C., the time may be reduced to two to ten hours.

Any of the llp-hydroxy-steroids, and particularly, the pregnanes and pregnenes may be converted to the corresponding A -anhydro-steroid. The reaction is very effective with the 1IB-hydrOXy-A -pregnenes, which makes the process of particular value, since heretofore a process for converting these types of compounds in high yield and in relatively short reaction time was not available. The presence of various substituents in the steroid molecule, such as 3,20-keto groups; 3,17a-hydroxy groups, and ring double bonds, does not interfere with the reaction. a 21-hydroxy group to convert it to the corresponding 21-ester compound. Particular examples of 11 B-hydroxysteroids are the 2l-esters of A -pregnene-llB,l7a,21-triol 3,20-dione, such as the acetate, propionate, formate, butyrate, benzoate, t-butylacetate, hemisuccinate and phenylacetate esters; M-pregnene-l1B,l7u-diol-3,20-dione, A pregnene-l 1/3-ol-3,20-dione; M-pregnene-l 1,8,21-diol-3,20 dione-21-acetate; acetate esters of A -pregnene-11p,17u, 21-triol-3,20-dione; A -androstene-11 8-ol-3,17-dione; A pregnene-l 1 3,17a,21-triol-3,20-dione; pregnane-l 113-01-3,

It is desirable, however, if there is 20-dione; pregnane 11 8,21 diol-3,20-dione-21-acetate; pnegnane-l 1B, 17a,2 l-triol-3,20-dione; allopregnane-l 1,8, 17u,2l-triol-3,20-dione; A -pregnene-3B,1 1,8-diol-20-one, and A -pregnene-l 1B,17a,2l-triol-3,20-dione-2l-acetate-3, ZO-bis-ethylene ketal.

The following examples are given for purposes of illustration:

Example 1 One gram of M-pregnene-llfi,l7a,2l-triol-3,20-dione- 2l-acetate was dissolved in 10 cc. of dry pyridine and 0.5 cc. of methanesulfonyl chloride was added. After standing for 16 hours, at normal room temperature, the reaction mixture was poured into 400 cc. of water and extracted with 100 cc. and 75 cc. of ethyl acetate. The ethyl acetate extract was washed with 2.5 N hydrogen chloride (100 cc.), water (100 cc.) and dried over magnesium sulfate. The solvent was removed in vacuo and afforded a crystalline residue which was recrystallized from methanol-chloroform. Melting point 221227 C. Infrared spectrum same as infrared spectrum of an authentic sample of A -pregnadiene-17a,21-diol-3,20- dione 21 acetate.

Example 2 Five grams of 4-pregnene-l1 6,17a,21-triol-3,20-dione 21-acetate were added to 25 cc. of dimethylformamide. The substance dissolved and then a solid separated. Pyridine (2 cc.) was added followed by 2.5 cc. of methanesulfonyl chloride. The reaction mixture was shaken for fifteen minutes and allowed to stand for 16 hours at normal room temperature. The reaction mixture was diluted with 500 cc. of ethyl acetate and Washed with 160 cc. of 2.5 N hydrogen chloride. An emulsion resulted and 300 cc. of methylene chloride was added. The methylene chloride-ethyl acetate solution was then washed with water and saturated sodium bicarbonate solution. After drying over magnesium sulfate anhydrous the solvent was removed in vacuo to give a crude yield of 5.0 gm. Recrystallization from methylene chloride-methanol afforded 3.0 g. (62%) of product, melting point Any departure from the above description, which conforms to the present invention, is intended to be included within the scope of the claims.

What is claimed is:

1. In a process for the conversion of a 21-1ower aliphatic carboxylic ester of A -pregnene-1l fl,17oc,21-t1i01- 3,20-dione to a 2l-lower aliphatic carboxylic ester of A -pregnadiene-17a,21-diol-3,20-dione by reaction with methanesulfonyl chloride in the presence of a tertiary amine, the improvement which comprises carrying out the reaction in the presence of dimethylformamide.

2. In a process for the conversion of a 2l-lower aliphatic carboxylic ester of A -pregnene-11fi,17a,21-triol 3,20-dione to a 21-lower aliphatic carboxylic ester of 13 -pregnadiene-17a,2l-diol-3,20-dione by reaction with methanesulfonyl chloride in the presence of pyridine, the improvement which comprises carrying out thereaction in the presence of dimethylformamide.

3. In a process for the conversion of A -pregnene- 11B,17a,21-triol-3,20-dione Zl-acetate to A -pregnadiene-l7a,21-diol-3,20-dione 21-acetate by reaction with methanesulfonyl chloride in the presence of pyridine, the improvement which comprises carrying out the reaction in the presence of dimethylformamide.

References Cited in the file of this patent UNITED STATES PATENTS 2,409,798 Reichstein Oct. 22, 1946 2,509,248 Sarett May 30, 1950 2,640,838 Wendler June 2, 1953 2,640,839 Wendler June 2, 1953 2,763,671 Fried et al Sept. 18, 1956 FOREIGN PATENTS 245,269 Switzerland July 1, 1947 OTHER REFERENCES Fieser et al.: Natural Products Related to Phenanthrene, 3rd edition, pages 99, 123, and 231 (1949). 

1. IN A PROCESS FOR THE CONVERSION OF A 21-LOWER ALIPHATIC CARBOXYLIC ESTER OF $4-PREGNENE-11B,17A,21-TRIOL3,20-DIONE TO A 21-LOWER ALIPHATIC CARBOXYLIC ESTER OF $4,9(11)-PREGNADIENE-17A,21-DIOL-3,20-DIONE BY REACTION WITH METHANESULFONYL CHLORIDE IN THE PRESENCE OF A TERTIARY AMINE, THE IMPROVEMENT WHICH COMPRISES CARRYING OUT THE REACTION IN THE PRESENCE OF DIMETHYLFORMAMIDE. 